Group II phospholipase A 2 (PLA 2) is an enzyme that has marked antibacterial properties in vitro. To define the role of group II PLA 2 in the defense against Staphylococcus aureus, we studied host responses in transgenic mice expressing human group II PLA 2 and group II PLA 2-deficient C57BL/6J mice in experimental S. aureus infection. After the administration of S. aureus, the transgenic mice showed increased expression of group II PLA 2 mRNA in the liver and increased concentration of group II PLA 2 in serum, whereas the PLA 2-deficient mice completely lacked the PLA 2 response. Expression of human group II PLA 2 resulted in reduced mortality and improved the resistance of the mice by killing the bacteria as indicated by low numbers of live bacteria in their tissues. Human group II PLA 2 was responsible for the bactericidal activity of transgenic mouse serum. These results suggest a possible role for group II PLA 2 in the innate immunity against S. aureus infection.